Abstract:
:The usefulness of a limited sampling method (LSM) to determine the bioequivalence of highly variable drugs with long half-lives was investigated. The LSM uses multiple linear regression of observed drug plasma concentrations versus area under the curve (AUC) or C(max) (peak plasma concentration) to obtain a best set of coefficients, concentration times and intercept based upon the regression coefficient, R(2), to predict the selected pharmacokinetic parameter (i.e. AUC or C(max)). The LSM, used successfully in clinical settings, has also been suggested for data analysis of in vivo bioequivalence studies. Because the method has not yet been thoroughly tested under many conditions likely to be encountered in bioequivalence studies, a further investigation of the method's applicability to bioequivalence determination was undertaken. In the present study, training and test data sets incorporating various levels of intrasubject variability in clearance (CL) with different ratios for fraction absorbed (Fa) of test and reference drug formulations were used to further evaluate the applicability of the limited sampling method (LSM) to the evaluation of bioequivalence for drugs with long half-lives of elimination. Both simulated (a one-compartment pharmacokinetic (PK) model with first-order elimination) and experimental data were used in the study. The results indicated that the determination of bioequivalence using the LSM was significantly influenced by the ratio of Fa(test)/Fa(reference) and by the level of intrasubject error (variability) in CL. Therefore, use of the LSM to determine bioequivalence of drugs with long half-lives and highly variable in CL seems suitable only for formulations that have point estimates of Fa(test)/Fa(reference) within the range of 0.9-1.10. Because the Fa ratio range would have to be verified through use of observed data obtained from a pilot study, the practical utility of the LSM in the determination of bioequivalence would be severely limited.
journal_name
Biopharm Drug Disposjournal_title
Biopharmaceutics & drug dispositionauthors
Jackson AJdoi
10.1002/bdd.275keywords:
subject
Has Abstractpub_date
2001-07-01 00:00:00pages
179-90issue
5eissn
0142-2782issn
1099-081Xpii
10.1002/bdd.275journal_volume
22pub_type
杂志文章abstract::Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment...
journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
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abstract::Based on the principle of superposition an expression has been established relating a drug concentration at steady-state to a concentration after a single dose. This relationship applies for drugs with linear pharmacokinetics given at equal dosage intervals and it is independent of the route of administration. The rel...
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journal_title:Biopharmaceutics & drug disposition
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journal_title:Biopharmaceutics & drug disposition
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abstract::The enantioselective pharmacokinetics of a new anxiolytic, pazinaclone (DN-2327), and its active metabolite, M-II, were studied in animals. In rats and dogs given racemic pazinaclone intravenously, the total clearance and volume of distribution of (S)-pazinaclone were lower than those of (R)-pazinaclone, whereas the o...
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abstract::An evaluation of the literature indicated that certain aspects of the disposition kinetics of iothalamate, important to the accurate determination of glomerular filtration rate in dogs and humans, remain to be resolved. The simultaneous clearances of iothalamate and inulin in 5 dogs were determined at three steady-sta...
journal_title:Biopharmaceutics & drug disposition
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abstract::The intestinal absorptive characteristics and the efflux mechanisms of candesartan (CDS), a novel angiotensin II type 1 receptor blocker, were investigated. The Caco-2 cells were used as models of the intestinal mucosa to assess uptake and transport of CDS. The determination of CDS was performed by HPLC-Flu. In the Ca...
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